2. Academic Validation
  3. Discovery of Novel Inhibitors of Uridine Diphosphate- N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients

Discovery of Novel Inhibitors of Uridine Diphosphate- N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients

  • J Med Chem. 2022 Feb 10;65(3):2149-2173. doi: 10.1021/acs.jmedchem.1c01684.
Marta Acebrón-García-de-Eulate 1,  Joan Mayol-Llinàs 2,  Matthew T O Holland 2,  So Yeon Kim 1,  Karen P Brown 3 4,  Chiara Marchetti 2,  Jeannine Hess 2,  Ornella Di Pietro 2,  Vitor Mendes 1,  Chris Abell 2,  R Andres Floto 3 4,  Anthony G Coyne 2,  Tom L Blundell 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, U.K.
  • 2 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • 3 Molecular Immunity Unit, Department of Medicine, MRC Laboratory of Molecular Biology, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, U.K.
  • 4 Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, CB23 3RE, UK.
PMID: 35080396 DOI: 10.1021/acs.jmedchem.1c01684
Abstract

Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this Infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel Antibiotics against P. aeruginosa. MurB is a promising target for novel Antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 μM (LE 0.35).

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